Hot of the Press July 2021

We have collated some great articles and material published over the last month. Click on the links below to read the  abstract or download the full paper.

Anatomy / Physiology /Pathophysiology

Advances in Lymphedema

Stanley G. Rockson. Circ Res. 2021 Jun 11;128(12):2003-2016
Lymphedema is a common, complex, and inexplicably underappreciated human disease. Despite a history of relative neglect by health care providers and by governmental health care agencies, the last decade has seen an explosive growth of insights into, and approaches to, the problem of human lymphedema. The current review highlights the significant advances that have occurred in the investigative and clinical approaches to lymphedema, particularly over the last decade. This review summarizes the progress that has been attained in the realms of genetics, lymphatic imaging, and lymphatic surgery. Newer molecular insights are explored, along with their relationship to future molecular therapeutics. Growing insights into the relationships among lymphedema, obesity, and other comorbidities are important to consider in current and future responses to patients with lymphedema.

Prevalence and Risk Factors

Lower-Limb Lymphedema after Sentinel Lymph Node Biopsy in Cervical Cancer Patients

David Cibula, Martina Borčinová, Simone Marnitz, Jiří Jarkovský, Jaroslav Klát, Radovan Pilka, Aureli Torné, Ignacio Zapardiel, Almerinda Petiz, Laura Lay, Borek Sehnal, Jordi Ponce, Michal Felsinger, Octavio Arencibia-Sánchez, Peter Kaščák, Kamil Zalewski, Jiri Presl, Alicia Palop-Moscardó, Solveig Tingulstad, Ignace Vergote, Mikuláš Redecha, Filip Frühauf, Christhardt Köhler, Roman Kocián. Cancers (Basel). 2021 May 13;13(10):2360. 

Download full paper

Weight management barriers and facilitators after breast cancer in Australian women: a national survey

Carolyn Ee1* , Adele Elizabeth Cave1, Dhevaksha Naidoo1, Kellie Bilinski1 and John Boyages2. BMC Women’s Health (2020) 20:140.

Background: Breast cancer is the most common cancer in women worldwide. Weight gain after breast cancer is associated with poorer health outcomes. The aim of this study was to describe how Australian breast cancer survivors are currently managing their weight.

Methods: Online cross-sectional survey open to any woman living in Australia who self-identified as having breast cancer, between November 2017 and January 2018.

Results: We received 309 responses. Most respondents described their diet as good/excellent and reported moderate-high levels of weight self-efficacy. Despite this, the proportion of overweight/obesity increased from 47% at time of diagnosis to 67% at time of survey. More than three quarters of respondents did not receive any advice on weight gain prevention at the time of diagnosis. 39% of women reported being less active after cancer diagnosis, and and few weight loss interventions were perceived to be effective. Facilitators were structured exercise programs, prescribed diets, and accountability to someone else, while commonly cited barriers were lack of motivation/willpower, fatigue, and difficulty maintaining weight. Women who cited fatigue as a barrier were almost twice as likely to be doing low levels of physical activity (PA) or no PA than women who did not cite fatigue as a barrier.

Conclusions: We report high levels of concern about weight gain after BC and significant gaps in service provision around weight gain prevention and weight management. Women with BC should be provided with support for weight gain prevention in the early survivorship phase, which should include structured PA and dietary changes in combination with behavioural change and social support. Weight gain prevention or weight loss programs should address barriers such as fatigue. More research is required on the effectiveness of diet and exercise interventions in BC survivors, particularly with regard to weight gain prevention.

Loco-regional therapy and the risk of breast cancer-related lymphedema: a systematic review and meta-analysis

Yan Lin, Ying Xu, Changjun Wang, Yu Song, Xin Huang, Xiaohui Zhang, Xi Cao, Qiang Sun
Breast Cancer. 2021 Jun 9. doi: 10.1007/s12282-021-01263-8. 

Background: This meta-analysis was designed to assess the association between two loco-regional therapies, regional nodal irradiation (RNI) and axillary lymph node dissection (ALND), and breast cancer-related lymphoedema (BCRL).

Methods: We searched PubMed, Science Direct, Embase, and BMJ databases for clinical studies published between January 1, 2010 and January 1, 2020, which assessed risk factors and incidence/prevalence of BCRL. Two investigators independently selected articles to extract relative data and calculate corresponding exact binomial 95% confidence intervals (CIs). In total, 93 articles were reviewed, from which 19 studies were selected. The extracted data were pooled using a random-effects mixed model.

Results: The incidence of lymphedema in the selected studies ranged from 3% to 36.7%, with a pooled incidence of 14.29% (95% CI 13.79-14.79). The summary odds ratio/risk ratio (OR/RR) of ALND vs. no-ALND was 3.67 (95% CI 2.25-5.98) with a heterogeneity (I2) of 81% (P < 0.00001). After excluding the studies with an abnormally high risk of lymphedema from self-reporting, the summary hazard ratio (HR) was 2.99 (95% CI 2.44-3.66) with no heterogeneity (I2 = 0%, P = 0.83). The summary OR/RR of patients with vs. without radiotherapy (RT) was 1.82 (95% CI 0.92-3.59), but the RR of RT to breast/chest vs. both axillary and supraclavicular areas was 2.66 (95% CI 0.73-9.70).

Conclusion: Regional nodal irradiation has a significantly higher risk for developing lymphedema than irradiation of the breast/chest wall. Axillary dissection and axillary RT have a similar risk for early-onset of breast cancer-related lymphoedema, although the risk trends higher for axillary dissection.

Lymphedema after Sentinel Lymph Node Biopsy: Who is at Risk?

Arda Isik, Atilla Soran, Ariel Grasi, Noran Barry, Efe Sezgin. Lymphat Res Biol. 2021 Jun 30.
Aim: Sentinel lymph node biopsy (SLNB) is the accepted approach to stage the clinically negative axilla. The incidence of lymphedema (LE) after SLNB is about 5%. We hypothesize that patients undergoing axillary excision of >5 lymph nodes (LNs) are at increased risk of developing LE.
Methods and Results: A single institution prospective breast cancer database was retrospectively reviewed from January 2013 to December 2017, to identify patients who underwent SLNB and were diagnosed with LE. Inclusion criteria was (1) de novo breast cancer, (2) SLNB in clinically node negative patients, and (3) no preoperative diagnosis LE of an extremity. Exclusion criteria was history of axillary lymph node dissection. Age, body mass index, tumor-node-metastasis status, surgery type, neoadjuvant or adjuvant chemotherapy, radiotherapy, and hormone therapy were analyzed. Of the 3325 patients identified, 2940 patients met the inclusion criteria and were included in the final analysis. Median follow-up time was 24 months. Forty-seven (2%) patients were diagnosed with LE, and nine patients (19%) had >5 LNs excised. LE was diagnosed in 3.7% of patients who had >5 LNs excised versus 1.4% of patients with ≤5 LNs excised. Incidence of LE was higher in patients with >5 LNs excision (p = 0.006).
Conclusion: Our study showed that patients have a higher likelihood of developing LE when >5 LNs are excised.

Assessment

The Interrater Reliability of the Scoring of the Lymphatic Architecture and Transport Through Near-InfraRed Fluorescence Lymphatic Imaging in Patients with Breast Cancer-Related Lymphedema

Sarah Thomis, Melissa Helberg, Jantine Kleiman, Tessa De Vrieze, An-Kathleen Heroes, Inge Fourneau, Nele Devoogdt. Lymphat Res Biol. 2021 Jun 2
Introduction: Of the 1.38 million women who are diagnosed every year with breast cancer worldwide, 21% will develop arm lymphedema. Near-infrared fluorescence lymphatic imaging (NIRFLI) is an effective method for real-time evaluation of the lymphatic system. Reliability studies of the scoring of this NIRFLI are lacking. The aim of this study is to investigate if evaluation of the superficial lymphatic architecture and transport in patients with breast cancer-related lymphedema through NIRFLI can be performed in a reliable way.
Methods and Results: The outcome parameters used to assess agreement were the presence of lymphatic transport from the injection sites, of dermal backflow patterns, of efferent lymphatic vessels, and of lymph nodes. The NIRFLI evaluations were scored before and after a break separately by two assessors. Twenty patients with lymphedema of the arm and/or hand were included. After the injection, there was weak to very strong agreement regarding the presence of transport from the injection sites (K = 0.459-1.000). The interpretation of the type of dermal backflow pattern varied from weak (WK = 0.452) to very strong agreement (WK = 1.000) between the two assessors. Agreement in the visualization of efferent lymphatic vessels was weak before and after the break (K = 0.490 and K = 0.571) and agreement regarding the presence of lymph nodes was very strong (K = 1.000).
Conclusion: Overall, there was moderate to strong agreement between the assessors when evaluating the lymphatic architecture and transport through NIRFLI.

Longitudinal, Long-Term Comparison of Single- versus Multipoint Upper Limb Circumference Periodical Measurements as a Tool to Predict Persistent Lymphedema in Women Treated Surgically for Breast Cancer: An Optimized Strategy to Early Diagnose Lymphedema and Avoid Permanent Sequelae in Breast Cancer Survivors

Cintia Furlan, Carolina Nascimben Matheus, Rodrigo Menezes Jales, Sophie F M Derchain, João Renato Bennini, Luís Otavio Sarian. Ann Surg Oncol. 2021 Jun 14

Purpose: We aim to evaluate whether upper limb (UL) circumference (ULC) and UL swelling sensation (ULSS) performed shortly after surgery or later on during follow-up can predict long-term/persistent forms of lymphedema in women who underwent surgery for breast cancer.

Patients and methods: Eighty-five women completed at least 24 months of follow-up. At each follow-up visit (1, 3, 6, 12, and 24 months after surgery), patients were tested for lymphedema using ULC and ULSS. Two different approaches to ULC were compared: (1) a “positive” lymphedema diagnosis if a difference ≥ 2 cm between the affected and contralateral UL was detected in at least two contiguous measurement points (MPs) and (2) a “positive” result if just one MP ≥ 2 cm. Patients were also questioned about their perception of weight, swelling, and/or tension (ULSS). The gold standard for long-term lymphedema was a water displacement difference between the UL ≥ 200 mL 24 months after surgery (ULWD).

Results: Twenty-four months after surgery, 19 (22.4%) women were diagnosed with long-term lymphedema. Using 24-month data, comparison of log-likelihoods denoted a clear superiority of the ULC approach 1 compared with 2 for the diagnosis of long-term lymphedema (p < 0.001). Using approach 1, the best prediction of a woman developing long-term lymphedema if she had a positive ULC in the follow-up was obtained at 6 months after surgery (posterior probability of 60%). Conclusions: Our study reveals that performing ULC 6 months after surgery, regarding as “positive” only women with a difference ≥ 2 cm at two contiguous MPs, is the best strategy to identify women at increased risk of later developing permanent forms of lymphedema.

Subclinical Lymphedema After Treatment for Breast Cancer: Risk of Progression and Considerations for Early Intervention

Loryn K Bucci, Cheryl L Brunelle, Madison C Bernstein, Amy M Shui, Tessa C Gillespie, Sacha A Roberts, George E Naoum, Alphonse G Taghian. Ann Surg Oncol. 2021 Jun 11.
Breast cancer-related lymphedema (BCRL) is a devastating complication of breast cancer (BC) treatment. The authors hypothesized that identifying subclinical lymphedema (SCL) presents an opportunity to prevent BCRL development. They aimed to assess rates of SCL progression (relative volume change [RVC], 5-10%) to BCRL (RVC, ≥10%) in women undergoing axillary surgery for BC via axillary lymph node dissection (ALND) or sentinel lymph node biopsy (SLNB).METHODS: Patients treated for BC were prospectively screened at preoperative baseline and throughout the follow-up period using the perometer. The cohort was stratified according to nodal surgery (ALND or SLNB) to analyze rates of progression to BCRL.RESULTS: The study cohort included 1790 patients. Of the 1359 patients who underwent SLNB, 331 (24.4%) experienced SCL, with 38 (11.5%) of these patients progressing to BCRL. Of the 431 patients who underwent ALND, 171 (39.7%) experienced SCL, with 67 (39.2%) of these patients progressing to BCRL. Relative to the patients without SCL, those more likely to experience BCRL were the ALND patients with early SCL (< 3 months postoperatively; hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.58-4.27; p = 0.0002) or late SCL (≥3 months postoperatively; HR, 3.14; 95% CI, 1.95-5.05; p < 0.0001) and the SLNB patients with early SCL (HR, 6.75; 95% CI, 3.8-11.98; p < 0.0001 or late SCL (HR, 3.02; 95% CI, 1.65-5.50; p = 0.0003).CONCLUSION: The study suggests that patients with SCL after axillary nodal surgery for BC are more likely to progress to BCRL than those who do not experience SCL. This presents a tremendous opportunity for early intervention to prevent BCRL and improve the quality of life for women treated for BC.

Evaluation and Management of Patients with Leg Swelling: Therapeutic Options for Venous Disease and Lymphedema

Kimberly Scherer, Neil Khilnani. Semin Intervent Radiol. 2021 Jun;38(2):189-193.
Lower extremity swelling is a common condition which has a variety of etiologies and can be challenging to diagnose and manage. Swelling is usually the result of the accumulation of interstitial fluid in the subcutaneous tissues. Common etiologies include systemic, superficial, and deep venous, and lymphatic disorders. Leg swelling can occur bilaterally or unilaterally, with venous disorders being one of the most common causes of unilateral lower extremity edema.

Relationship Between the Circumference Difference and Findings of Indocyanine Green Lymphography in Breast Cancer-Related Lymphedema

Hideki Tokumoto, Shinsuke Akita, Yoshitaka Kubota, Nobuyuki Mitsukawa. Ann Plast Surg. 2021 Jun 23.

Background: Breast cancer-related lymphedema (BCRL) is a common complication. Indocyanine green (ICG) lymphography has been performed to assess lymphatic functionality. We found that some BCRL patients had a difference in circumference in partial regions only. The purpose of this study was to evaluate the patients with BCRL about the correlation between the difference in circumference and the findings of ICG lymphography.

Methods: One hundred fifty-five patients with unilateral BCRL were enrolled in this study. We evaluated the differences in circumference taken at 4 parts on the upper limb (at around the wrist, forearm, elbow, and brachium). The difference in circumference was evaluated between the affected part (Caf) and the unaffected part (Cun). We calculated the circumference difference rate (CDR) as follows: CDR = 100 (Caf – Cun)/Caf. First, we classified each part of all BCRL patients (620 parts) based on the findings of ICG lymphography (linear, collateral, dermal back flow [DBF], and no enhancement) and evaluated the correlation. Second, in the patients with partial volume change, we compared the mean CDR in each part.

Results: One hundred six parts were of a linear pattern, 31 parts were collateral, 350 parts were DBF, and 133 parts had no enhancement. The mean CDR of each finding was 3.3% in linear, 4.0% in collateral, 9.6% in DBF, and 9.4% in no enhancement. There was no significant difference between linear and collateral (P = 0.62), DBF, and no enhancement (P = 0.89) patterns. However, there was a significant difference between linear or collateral and DBF or no enhancement (all P < 0.001). In the 22 patients with distal DBF and proximal linear, the CDR was significantly higher in the forearm compared with the brachium (6.4% and 3.0%; P = 0.003). In the 26 patients with distal linear and proximal DBF, the CDR was significantly higher in the brachium compared with the forearm (4.3% and 7.7%; P = 0.005). Conclusions: There was a significant correlation between the difference in circumference and the severity of ICG findings.

Development and Psychometric Validation of a Patient-Reported Outcome Measure for Arm Lymphedema: The LYMPH-Q Upper Extremity Module

Anne F Klassen, Elena Tsangaris, Manraj N Kaur, Lotte Poulsen, Louise M Beelen, Amalie Lind Jacobsen, Mads Gustaf Jørgensen, Jens Ahm Sørensen, Dalibor Vasilic, Joseph Dayan, Babak Mehrara, Andrea L Pusic. Ann Surg Oncol. 2021 Jul 5

Background: A multiphased mixed-methods study was performed to develop and validate a comprehensive patient-reported outcome measure (PROM) for arm lymphedema in women with breast cancer (i.e., the LYMPH-Q Upper Extremity Module).

Methods: Qualitative interviews (January 2017 and June 2018) were performed with 15 women to elicit concepts specific to arm lymphedema after breast cancer treatment. Data were audio-recorded, transcribed, and coded. Scales were refined through cognitive interviews (October and Decemeber 2018) with 16 patients and input from 12 clinical experts. The scales were field-tested (October 2019 and January 2020) with an international sample of 3222 women in the United States and Denmark. Rasch measurement theory (RMT) analysis was used to examine reliability and validity.

Results: The qualitative phase resulted in six independently functioning scales that measure arm symptoms, function, appearance, psychological function, and satisfaction with information and with arm sleeves. In the RMT analysis, all items in each scale had ordered thresholds and nonsignificant chi-square p values. For all the scales, the reliability statistics with and without extremes for the Person Separation Index were 0.80 or higher, Cronbach’s alpha was 0.89 or higher, and the Intraclass Correlation Coefficients were 0.92 or higher. Lower (worse) scores on the LYMPH-Q Upper Extremity scales were associated with reporting of more severe arm swelling, an arm problem caused by cancer and/or its treatment, and wearing of an arm sleeve in the past 12 months.

Conclusions: The LYMPH-Q Upper Extremity Module can be used to measure outcomes that matter to women with upper extremity lymphedema. This new PROM was designed using a modern psychometric approach and, as such, can be used in research and in clinical care.

The impact of lymphedema on health-related quality of life up to 10 years after breast cancer treatment

Mads G Jørgensen, Navid M Toyserkani, Frederik G Hansen, Anette Bygum, Jens A Sørensen. NPJ Breast Cancer. 2021 Jun 1;7(1):70

Download full paper

Analysis of Spinal Dysfunction in Breast Cancer Survivors with Lymphedema

Shinde Sandeep Babasaheb, Kulkarni Kajol Rajesh, Kolekar Shital Yeshwant, Sanjaykumar Patil. Asian Pac J Cancer Prev. 2021 Jun 1;22(6):1869-1873.

Download full paper

Physical findings and tests useful for differentiating lymphedema

Eriko Kamijo, Kosuke Ishizuka, Kiyoshi Shikino, Eri Sato, Masatomi Ikusaka
J Gen Fam Med. 2021 Feb 17;22(4):227-228

Download full paper

Determination of Bioelectrical Impedance Thresholds for Early Detection of Breast Cancer-related Lymphedema

Siyao Liu, Quanping Zhao, Xinmei Ren, Ying Cui, Houpu Yang, Siyuan Wang, Miao Liu, Shu Wang. Int J Med Sci. 2021 Jun 11;18(13):2990-2996

Download full paper

Management Strategies

Lymphedema rehabilitation: Provision and practice patterns among service providers: National survey

Mohammed T.A. Omar, Nouf M Al-Dhwayan, Rehab F M Gwada, Jane M. Armer
Int Wound J. 2021 Jun 1.

Download full paper

The Effects of Kinect-Enhanced Lymphatic Exercise Intervention on Lymphatic Pain, Swelling, and Lymph Fluid Level

Mei R. Fu, Melissa L McTernan, Jeanna M Qiu, Eunjung Ko, Simay Yazicioglu, Deborah Axelrod, Amber Guth, Zhipeng Fan, Anna Sang, Christine Miaskowski, Yao Wang. Integr Cancer Ther. 2021 Jan-Dec;20:15347354211026757.

Download full paper

Velcro compression wraps as an alternative form of compression therapy for venous leg ulcers: a review

Amy Cox, Chrissie Bousfield. Br J Community Nurs. 2021 Jun 1;26(Sup6):S10-S20.
The first-line treatment for venous leg ulcers (VLUs) is compression therapy, most commonly, with compression bandages. A similar treatment measure is used for lymphoedema in the form of Velcro compression wraps (VCWs). However, the use of VCWs for VLUs is less evident, and a direct comparison to compression bandaging is not evident. This review explores the evidence to support the use of VCWs for the treatment of VLUs in order to raise awareness of alternative forms of compression therapy. Nine primary research studies were analysed, from which four key themes emerged: quality of life, cost of treatment, ulcer healing time and pressure maintenance. The findings suggest that VCWs decrease material costs by at least 50%, and further savings may be realised by reducing the costs associated with nursing time. The benefits of promoting self-care, maintaining compression, and eliciting greater healing rates are clearly evident, and the impact on quality of life is substantiated.

Breast cancer-related lymphedema patient and healthcare professional experiences in lymphedema self-management: a qualitative study

Huihui Zhao, Yanni Wu, Chunlan Zhou, Wenji Li, Xiaojin Li, Liling Chen. Support Care Cancer. 2021 Jul 5.

Purpose: Breast cancer-related lymphedema (BCRL) self-management plays an important role in the lymphedema therapy. However, clinical knowledge of BCRL self-management remains minimal. This study aims to explore the experience surrounding lymphedema self-management from the perspectives of BCRL patients and healthcare professionals.

Methods: Semi-structured interviews were implemented with BCRL patients and healthcare professionals. Audio-recordings of interviews were transcribed verbatim and thematic analysis was undertaken to analyze the interview data.

Results: Thirteen BCRL patients (aged 34-65 years) and nine healthcare professionals (2 physicians, 4 nurses, and 3 lymphedema therapists) were interviewed. Five themes emerged from interviews with participants: knowledge-attitude-practice surrounding lymphedema self-management, emotional reactions towards lymphedema self-management, factors influencing lymphedema self-management, support needs for lymphedema self-management, healthcare professional support of BCRL self-management.

Conclusions: This study showed knowledge-attitude-practice, feelings, influencing factors, roles, dilemmas, and support needs regarding BCRL self-management. Greater effort is required for healthcare professionals to strengthen the lymphedema self-management. Providing more educational program and holistic support, and strengthening the facilitators and controlling the barriers might benefit promoting lymphedema self-management. Likewise, healthcare professionals need adequate training to be able to meet patients’ self-management support needs.

Children and young people with lymphoedema: Quality of life tool updateCompilation of recent publications on tissue dielectric constant (TDC)